Beyond GLP-1s: Combination Therapy, New Hormones Reshape Obesity Treatment

The first wave of blockbuster obesity medications, including semaglutide (Ozempic, Wegovy) and tirzepatide (Zepbound, Mounjaro), transformed weight loss by achieving levels once thought possible only with bariatric surgery.

Now, emerging treatments aren’t necessarily focused on more weight loss, but better tolerability, preservation of muscle and bone, and eventually, more tailored treatment based on a patient’s individual biology.

“You either need to be more effective or more tolerable,” says Brian Wojeck, MD, an endocrinologist and obesity medicine specialist at Yale Medicine, describing what it takes for a new therapy to stand out in a crowded field.

Some of these new treatments combine multiple hormones in a single drug. Others introduce different stand-alone hormones altogether. Tirzepatide, for example, combines two hormones: glucagon-like peptide-1 (GLP-1), which promotes fullness, and glucose-dependent insulinotropic polypeptide (GIP), which helps regulate metabolism and blood sugar. It was the first widely used obesity medication to target more than one hormonal pathway, helping establish the idea that combining hormones could improve results.

Here’s what Yale Medicine specialists say about the hormones and combinations being studied next—and what patients should know about where the research stands.

Glucagon is a hormone that raises blood sugar—which may sound like an odd addition to a weight-loss drug. But in combination with other hormones, researchers believe glucagon may provide an added metabolic boost, help increase how many calories the body burns (energy expenditure), and reduce fat stored in the liver.

John Morton, MD, MPH, chief of Yale Medicine Bariatric and Minimally Invasive Surgery and a board-certified obesity medicine specialist, compares this approach to balancing a gas pedal and a brake: different hormones working together to influence appetite, metabolism, and blood sugar.

One of the most closely watched experimental drugs is retatrutide, which targets three hormones—GLP-1, GIP, and glucagon—at once. Retatrutide is not yet approved by the U.S. Food and Drug Administration (FDA). In clinical trials, it has produced weight loss approaching what’s typically seen with bariatric surgery.

Still, Dr. Morton cautions that greater weight loss is only part of the equation; tolerability and long-term adherence remain critical considerations.

Amylin is a hormone released alongside insulin that also promotes fullness and helps regulate blood sugar. Early studies suggest amylin-based therapies may produce meaningful weight loss with fewer gastrointestinal side effects than some existing medications.

Amylin itself isn’t new, Dr. Morton notes. A synthetic version was approved for diabetes in 2005, but it required frequent injections and never gained widespread use. Newer, longer-lasting amylin-based therapies are now in development.

“It now works a lot like a GLP-1 in that it slows down gastric emptying [how quickly food leaves the stomach] and helps regulate blood sugar,” he says. “But here’s the kicker: In studies, it appears to be very well tolerated. In one study, the side effects were equivalent to those of the placebo, which is quite remarkable.”

In early studies, amylin-based therapies have produced weight loss of about 15% of body weight—less than the nearly 30% reported in some studies of newer triple-hormone medications. But Dr. Morton says even modest weight loss can have real benefits.

“As little as 5% weight loss improves high blood sugar and high blood pressure,” he says. “And 15% can help people get rid of fatty liver disease and sleep apnea.”

Researchers are also studying whether amylin may benefit bone health while still producing meaningful weight loss, Dr. Morton says, though more research is needed.

While these early results are encouraging, Dr. Wojeck cautions that scientists still need real-world experience and larger studies to understand how amylin and other emerging therapies will perform in everyday practice, outside the setting of a clinical trial.

Gastrointestinal side effects—like nausea and digestive discomfort—remain among the most common reasons patients stop treatment. At the same time, researchers are studying how significant weight loss affects muscle mass and bone health, and whether future therapies can better protect both.

For obesity specialists, success is about more than the number on the scale. Dr. Wojeck says physicians are increasingly focused on long-term health outcomes, including:

• Cardiovascular disease
• Diabetes
• Fatty liver disease
• Sleep apnea

“Weight loss is no longer, in my opinion, the goal with these drugs. The goal is tolerability,” Dr. Morton says.

Significant weight loss can also lead to some loss of muscle mass and reduced bone density over time, Dr. Wojeck explains. In simple terms, a lighter body requires less muscle to move it and places less stress on bones—which can affect how the body maintains both.

That doesn’t necessarily mean worse physical function, though. When weight loss is paired with adequate nutrition, exercise, and especially strength training, many patients experience improvements in mobility and overall function, Dr. Wojeck says.

As researchers develop new hormone therapies and combinations, a bigger question remains: Why do some patients respond dramatically to certain medications while others do not?

“The main problem is that we really don’t understand obesity enough,” Dr. Morton says. “There is a lot of variation in response to therapy.”

Roughly 10% of patients in clinical trials lose less than 5% of their body weight, Dr. Morton notes—a sign of how much researchers still have to learn about the underlying biology of obesity.

Dr. Wojeck sees that same variability in his own patients. Some who don’t respond well to newer obesity medications go on to lose substantial weight with older therapies instead.

“The truth is that everyone’s obesity is unique,” he says.

Today, choosing a treatment often still involves some trial and error. “We’re not yet at the point where we can say, ‘This medicine will work well for you,’” Dr. Wojeck says.

Still, both physicians believe the field is moving in that direction. Dr. Morton predicts that doctors will eventually have a “family of drugs” to choose from, as researchers work toward tailoring obesity treatment to each patient’s individual biology and health needs.

Most of the therapies described here—including retatrutide and newer amylin-based drugs—are still in clinical trials and aren’t available outside of research settings. If you’re currently taking a GLP-1 medication, it’s worth checking in with your doctor if:

• Side effects, like nausea or digestive symptoms, are hard to manage
• You aren’t seeing the results you expected after several months
• You’re considering stopping or switching treatment

You don’t need to make changes on your own. An obesity medicine specialist can help you weigh options among currently approved medications while researchers continue to evaluate the next generation of obesity treatments.